Production of chirally pure amino alcohol intermediates, derivatives thereof, and uses thereof

ABSTRACT

A method of selectively preparing a chiral 2S-amino alcohol useful in preparation of an amide sulfonated or acylated with alkyl, substituted aryl or substituted heteroaryl is described. The method involves reacting a di-tert-butyl diazene-1,2-dicarboxylate with a (4S)-4-benzyl-3-[(S)-trifluoromethyl-alkyl substituted alkanoyl]-1,3-oxazolidin-2-one to afford a di-tert-butyl 1-(1S,2S)-([(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-carbonyl}-trifluoromethyl-alkyl substituted alkyl)hydrazine-1,2-dicarboxylate. This dicarboxylate is then reduced to yield di-tert-butyl 1-(1S,2S)-[trifluoromethyl-alkyl substituted alkyl]hydrazine-1-(hydroxymethyl)-1,2-dicarboxylate. The resulting product is deblocked with an acid to yield the acid addition salt of (2S,3S)-trifluoro-hydrazino-methyl alkan-1-ol. The acid addition salt of (2S,3S)-trifluoro-2-hydrazino-methyl alkan-1-ol is hydrogenated in the presence of a suitable metal catalyst to yield the amino alcohol (2S,3S)-2-amino-trifluoro-methyl alkan-1-ol HCl.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/787,962, filed Apr. 18, 2007 now U.S. Pat. No. 7,598,422, whichclaims the benefit under 35 USC 119(e) of U.S. Provisional PatentApplication No. 60/793,896, filed Apr. 21, 2006. These priorityapplications are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is the most common form of dementia (loss ofmemory) in the elderly. The main pathological lesions of AD found in thebrain consist of extracellular deposits of beta amyloid protein in theform of plaques and angiopathy and intracellular neurofibrillary tanglesof aggregated hyperphosphorylated tau protein. Recent evidence hasrevealed that elevated beta amyloid levels in brain not only precede taupathology but also correlate with cognitive decline. Further suggestinga causative role for beta amyloid in AD, recent studies have shown thataggregated beta amyloid is toxic to neurons in cell culture and has adetrimental effect on memory. This suggests that reducing beta amyloidlevels is a viable therapeutic strategy for the treatment of AD.

Beta amyloid protein is composed mainly of 39-42 amino acid peptides andis produced from a larger precursor protein called amyloid precursorprotein (APP) by the sequential action of the proteases beta and gammasecretase. Although rare, cases of early onset AD have been attributedto genetic mutations in APP that lead to an overproduction of eithertotal beta amyloid protein or its more aggregation-prone 42 amino acidisoform. Furthermore, people with Down's syndrome possess an extrachromosome that contains the gene that encodes APP and thus haveelevated beta amyloid levels and invariably develop AD later in life.

Methods of producing substituted heteroaryl sulfonamide compounds usefulas beta amyloid inhibitors have been described [U.S. Pat. No. 6,610,734;U.S. Pat. No. 6,878,742]. These methods have included the constructionof an acylated Evans oxazolidone chiral auxiliary, which is thenconverted to the corresponding enolate and electrophilically aminatedwith trisyl azide to afford the desired, key intermediate (J. Am. Chem.Soc. 109: 6881-6883 (1987)). The azide intermediate is then hydrolyzedto the a-azido acid and reduced to the chirally pure a-amino acid whichcan be converted to the corresponding N-sulfonyl 2-amino alcohols.However, this method utilizes reagents, notably, the trisyl azide, whichare not suitable for large scale production.

What are needed are improved methods of making compounds that areeffective in lowering beta amyloid production.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a method of producing a 1S,2S-amino alcohol having two chiral centers, which is useful inproduction of a number of target compounds. The method of the inventionavoids reagents that cannot be used for scale-up and allows thepreparation of the target compounds without chromatography and excellentchiral purity, chemical purity and stability.

The invention further provides a method for stereoselectivelyintroducing an S-nitrogen in a chiral 2S-amino alcohol in order toprepare target compounds having a 1S,2S configuration.

Other aspects and advantages of the invention will be apparent from thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods of producing a 1S,2S amino alcohol, orsalt thereof, having at least one chiral center from the amino alcoholis sulfonylated or acylated with residues containing an alkyl,substituted aryl or substituted heteroaryl group.

Amino alcohols having two chiral centers, salts and derivatives, andintermediates thereof, may be prepared according to the presentinvention. Typically, the 2S-amino alcohols are characterized by theformula:

Suitably, in the above formulae, n is 0 to about 10; R₁ and R₂ areindependently selected from the group consisting of lower alkyl,substituted lower alkyl, lower alkenyl, CF₃, cycloalkyl, substitutedcycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl,CH₂cycloalkyl, CH₂-3-indole, CH(loweralkyl)-2-furan,CH(loweralkyl)-4-methoxyphenyl, CH(loweralkyl)phenyl, orCH(OH)-4-SCH₃-phenyl; and R′ is selected from among H, lower alkyl,substituted lower alkyl, lower alkenyl, CF₃, heterocycle, substitutedheterocycle, phenyl, substituted phenyl, benzyl, substituted benzyl,cycloalkyl, and substituted cycloalkyl, among other suitable groups. Inone embodiment, the substituted lower alkyl is a fluoroalkyl. Thesecompounds may be readily converted to desired compounds including,without limitation, the corresponding aldehydes, oximes, andpharmaceutically acceptable salts, hydrates, and prodrugs thereof.However, the compounds produced by the methods of the present inventionare not limited by the above formulae.

As used herein, the term “chirally pure” refers to compounds which arein about 100% S-(or R) enantiomeric form as measured by chiral highperformance liquid chromatography (HPLC). Although many of the examplesprovided herein illustrate formation of the S-enantiomer, the presentinvention can give the R enantiomer if the auxillary is changed. Othermethods of measuring chiral purity include conventional analyticalmethods, including specific rotation, and conventional chemical methods.However, the technique used to measure chiral purity is not a limitationon the present invention.

As used herein, the term “pharmaceutically useful” refers to compoundshaving a desired biological effect, whether as a therapeutic, immunestimulant or suppressant, adjuvant, or vaccinal agent. Similarly, avariety of compounds which are suitable for use in non-pharmaceuticalapplications, e.g., a diagnostic, a marker, among others may be producedby the method of the invention. However, other pharmaceutically usefulcompounds may be produced by this method.

The compounds produced by the present invention and any target compoundsinto which they are converted can be used in the form of salts derivedfrom pharmaceutically or physiologically acceptable acids or bases.Other salts include salts with alkali metals or alkaline earth metals,such as sodium (e.g., sodium hydroxide), potassium (e.g., potassiumhydroxide), calcium or magnesium.

These salts, as well as other compounds produced by the method of theinvention may be in the form of esters, carbamates and otherconventional “pro-drug” forms, which, when administered in such form,convert to the active moiety in vivo. In one desirable embodiment, theprodrugs are esters. See, e.g., B. Testa and J. Caldwell, “ProdrugsRevisited: The “Ad Hoc” Approach as a Complement to Ligand Design”,Medicinal Research Reviews, 16(3):233-241, ed., John Wiley & Sons(1996).

The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having one to tencarbon atoms, preferably one to eight carbon atoms and, most preferably,one to six carbon atoms; as used herein, the term “lower alkyl” refersto straight- and branched-chain saturated aliphatic hydrocarbon groupshaving one to six carbon atoms;

The terms “substituted alkyl”, as just described having from one tothree substituents selected from the group including halogen, CN, OH,NO₂, amino, aryl, heterocyclic, substituted aryl, substitutedheterocyclic, alkoxy, substituted alkoxy, aryloxy, substituted alkyloxy,alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. Thesesubstituents may be attached to any carbon of an alkyl, alkenyl, oralkynyl group provided that the attachment constitutes a stable chemicalmoiety.

As used herein, a fluoroalkyl is a substituted alkyl, which issubstituted with one to three fluorine atoms. As used herein,trifluoromethyl, i.e., CF₃, refers to a fluoroalkyl having one carbonatom, which carbon atom is the point of attachment.

The term “aryl” is used herein to refer to a carbocyclic aromaticsystem, which may be a single ring, or multiple aromatic rings fused orlinked together as such that at least one part of the fused or linkedrings forms the conjugated aromatic system. The aryl groups include, butare not limited to, phenyl, naphthyl, biphenyl, anthryl,tetrahydronaphthyl, phenanthryl, and indane.

The term “substituted aryl” refers to aryl as just defined having one tofour substituents from the group including halogen, CN, OH, NO₂, amino,alkyl, cycloalkyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl,alkylcarboxy, alkylamino, and arylthio.

The term “substituted benzyl” refers to a benzyl (Bn) group, havingsubstituted on the benzene ring, one to five substituents from the groupincluding halogen, CN, OH, NO₂, amino, alkyl, cycloalkyl, alkoxy,aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,and arylthio.

The term “heterocyclic” is used herein to describe a stable 4- to7-membered monocyclic or a stable multicyclic heterocyclic ring which issaturated, partially unsaturated, or unsaturated, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupincluding N, O, and S atoms. The N and S atoms may be oxidized. Theheterocyclic ring also includes any multicyclic ring in which any ofabove defined heterocyclic rings is fused to an aryl ring. Theheterocyclic ring may be attached at any heteroatom or carbon atomprovided the resultant structure is chemically stable. Such heterocyclicgroups include, for example, tetrahydrofuran, piperidinyl, piperazinyl,2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl,indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, isoquinolinyl, andtetrahydrothiopyran.

The term “substituted heterocyclic” is used herein to describe theheterocyclic just defined having one to four substituents selected fromthe group which includes halogen, CN, OH, NO₂, amino, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy,aryloxy, substituted aryloxy, alkyloxy, substituted alkyloxy,alkylcarbonyl, substituted alkylcarbonyl, alkylcarboxy, substitutedalkylcarboxy, alkylamino, substituted alkylamino, arylthio, orsubstituted arylthio.

The term “substituted cycloalkyl” is used herein to describe acarbon-based ring having more than 3 carbon-atoms which forms a stablering and having from one to five substituents selected from the groupconsisting of halogen, CN, OH, NO₂, amino, alkyl, substituted alkyl,alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy,alkylamino, substituted alkylamino, arylthio, heterocyclic, substitutedheterocyclic, aminoalkyl, and substituted aminoalkyl.

The term “alkoxy” is used herein to refer to the O(alkyl) group, wherethe point of attachment is through the oxygen-atom and the alkyl can beoptionally substituted. The term “aryloxy” is used herein to refer tothe O(aryl) group, where the point of attachment is through theoxygen-atom and the aryl, can be optionally substituted. The term“alkylcarbonyl” is used herein to refer to the CO(alkyl) group, wherethe alkyl can be optionally substituted and the point of attachment isthrough the carbon atom of the carbonyl group. The term “alkylcarboxy”is used herein to refer to the COO(alkyl) group, where the alkyl can beoptionally substituted and the point of attachment is through the carbonatom of the carboxy group. The term “aminoalkyl” refers to bothsecondary and tertiary amines wherein the alkyl or substituted alkylgroups, containing one to eight carbon atoms, which may be either sameor different, and the point of attachment is on the nitrogen atom.

The term “halogen” refers to Cl, Br, F, or I.

The term “strong non-nucleophilic base” refers to a basic reagent, whichdoes not act as a nucleophile towards the reactants utilized in thereaction. A number of non-nucleophilic bases are known in the art andinclude sodium hydride, potassium hydride, lithium diisopropylamide andpotassium hexamethyldisilazide.

The term “aqueous base” refers to a solution composed of, at a minimum,a base and water. A number of bases which readily dissolve in water areknown in the art and include alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide or potassium hydroxide, among others. Theaqueous base solution may further contain other reagents which do notinterfere with the reactions of the present invention, and includeorganic solvents such as tetrahydrofuran, methanol, ethanol, orhydrocarbon solvents, salts such as sodium chloride, and buffers, amongothers.

The term “aqueous acid” refers to a solution composed of, at a minimum,an acid and water. The aqueous acid solution may further contain otherreagents which do not interfere with the reactions of the presentinvention.

The term “strong acid” or “strong base” refers to an acid or base thatis highly ionized in solution. Common strong acids include HCl, HBr, HI,HNO₃, H₂SO₄, and HClO₄. Common strong bases include hydroxides of thealkali metals (Li, Na, K, Cs) and hydroxides of the heavy alkalineearths (Ca, Sr, Ba).

The term “inorganic” acid or “inorganic” base includes acids and baseswhich do not contain carbon.

The term “organic solvent” may include any carbon-containing solventknown in the art, which does not react with the reagents utilized in thereaction and includes saturated hydrocarbon solvents, unsaturatedhydrocarbon solvents, including aromatic hydrocarbon solvents, alcohols,halocarbons, ethers and acetates, among others.

SYNTHESIS

The synthetic methods of the invention are described in the followingscheme. These methods, together with synthetic methods known in thesynthetic organic arts or variations of these methods by one skilled inthe art are used in the present invention. See, generally, ComprehensiveOrganic Synthesis, “Selectivity, Strategy & Efficiency in Modern OrganicChemistry,” ed., I. Fleming, Pergamon Press, New York (1991);Comprehensive Organic Chemistry, “The Synthesis and Reactions of OrganicCompounds”, ed. J. F. Stoddard, Pergamon Press, New York (1979)). In thefollowing scheme, the term “BOC” refers to a t-butyl oxy carbonyl group.

The acid in the starting material is activated. As illustrated, an acylhalide is prepared. Alternative methods, e.g., preparation of a mixedanhydride, may be utilized. As illustrated in Scheme I, a dialkylazodicarboxylate is reacted at the carbanion at the 2 position undercold conditions with a (4S)-4-benzyl-3-[(S)-trifluoromethyl-alkylsubstituted alkanoyl]-1,3-oxazolidin-2-one which has been dissolved inlithium diisopropyl amide (LDA) or potassium bis(trimethyl)silylamide,and a suitable solvent system (e.g., tetrahydrofuran, THF). Thisapproach was reported by the Evans group (Tetrahedron 44, (1988), 5525,JACS, 104, (1982), 1734). In the example provided herein, di-tert-butylazodicarboxylate in used for ease of removal in a suitable reaction. Inanother embodiment the substituent may be dibenzyl,bis(2-trichloroethyl), dialkyl or diaryl or another suitable groupselected by one of skill in the art. Similarly, in the example providedherein, a 4(S)-benzyl oxazolidinone is used as the chiral auxillaryhowever, other 4- and 3,4 disubstituted chiral oxazolidines (e.g.,(4S)-4-phenyloxazolidinone) known to one skilled in the art may be used.

In one embodiment, the solvent system for the LDA comprisestetrahydrofuran (THE). The solvent may also contain other solventsincluding, e.g., heptane, ethylbenzene, or mixtures thereof. Typically,THF is the primary component of the solvent system. The reaction of thedi-tert-butyl diazene-1,2-dicarboxylate with the anion formed from theacylated oxazolidinone may be quenched with glacial acetic acid. The THFis removed by distillation and replacement with toluene, separation ofthe layers and washing twice with saturated NaHCO₃ and water provides atoluene solution. The toluene is removed by vacuum distillation. Theresulting product is a di-tert-butyl1-(1S,2S)-([(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-carbonyl}-trifluoromethyl-alkylsubstituted alkyl)hydrazine-1,2-dicarboxylate. This methodology can alsobe applied to nonfluorinated systems.

The resulting di-tert-butyl1-(1S,2S)-([(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-carbonyl}-trifluoromethyl-alkylsubstituted alkyl)hydrazine-1,2-dicarboxylate is reduced. The reductioninvolves reaction of dissolved di-tert-butyl1-(1S,2S)-(1-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-carbonyl}-trifluoromethyl-alkylsubstituted alkyl)hydrazine-1,2-dicarboxylate and LiBH₄ intetrahydrofuran and water, or, alternatively, t-butyl methyl ether(TBME) and water. Typically, the reaction is allowed to proceed for atleast about 16 hours prior to adding an acid (e.g., HCl) to the reactionmixture. The aqueous phase is separated and the organic phase is washed.The solution is then stripped until a solid is obtained. The solution iscooled, the solid filtered, and washed with acetonitrile. Thereafter, asample of the solid may be assayed to ensure that the product has amelting point of greater than 181° C.

The resulting di-tert-butyl 1-(1S,2S)-[trifluoromethyl-alkyl substitutedalkyl]hydrazine-1-(hydroxymethyl)-1,2-dicarboxylate is deblocked toyield the acid addition salt of (2S,3S)-trifluoro-hydrazino-methylalkan-1-ol. Deblocking is achieved by mixing the di-tert-butyl1-(1S,2S)-[trifluoromethyl-alkyl substitutedalkyl]hydrazine-1-(hydroxymethyl-1,2-dicarboxylate with a strong acid,e.g., HCl. Typically, this is performed at a temperature of about 30° C.to 50° C. Alternatively, if the dibenzyl ester is utilized rather than atert-butyl ester, then other deblocking methods can be used, e.g., O.Pouparbid, C. Greck and J-P, Genet, Synlett, 1998, 1279.

The amino alcohol (2S,3S)-2-amino-trifluoromethyl methyl alkan-1-ol HClis hydrogenated with the acid addition salt of(2S,3S)-trifluor-2-hydrazino-methyl alkan-1-ol in the presence ofsuitable metal catalyst. Examples of suitable metal catalysts include,e.g., PtO₂, Pd, and RaNi. Other catalysts can be readily substituted.

In one embodiment, the method of the invention further comprises thestep of triturating the resulting product of in a suitable solvent toremove trapped metal contaminants from the catalyst. This can beaccomplished using acetonitrile or 20% (w/w) acetonitrile/EtOAc toremove the amino alcohol-catalyst complex from the primarily insolubleamino alcohol HCl salt.

Advantageously, the method of the invention provides a novel method ofconstructing an alpha amino acylated Evans oxazolidone, which avoidstrisyl azide and other reagents, which are not suitable for large scaleproduction. The resulting product is useful in the synthesis of avariety of pharmaceutically useful target compounds where the amine fromthe amino alcohol is reacted to form a sulfonamide or acylated withalkyl, substituted aryl or substituted heteroaryl.

The resulting amino alcohol can then be used in the synthesis of avariety of desirable products. For example, the amino alcohol producedaccording to the method of the invention can be used to produce thesubstituted aryl or substituted heteroaryl sulfonamide compoundsdescribed in Porte et al, U.S. Provisional Patent Application No.60/793,852, filed Apr. 21, 2006, filed on the same date herewith,entitled “Trifluoromethyl-Containing Phenylsulfonamide Beta AmyloidInhibitors”, U.S. Pat. Nos. 6,878,742, 6,610,734, WO 092152A1. Suitabletechniques for the acylation reactions described herein may be readilyselected by one of skill in the art. See generally, Vogel's Textbook ofPractical Organic Chemistry and Greene, Theodora W.; Wuts, Peter G. M.Protective Groups in Organic Synthesis. 2nd Ed. (1991).

For substituted aryl or heteroaryl sulfonamide compounds such as thosedescribed in the exemplary documents described above, the 2S-aminoalcohol or the salt thereof may be reacted with a suitable solvent and atertiary base in the presence of the substituted aryl sulfonyl halide(e.g., sulfonyl chloride) or substituted heteroaryl sulfonyl sulfonateester (e.g., pentafluorophenylsulfonyl ester).

Examples of suitable solvents include dichloromethane, THF,methyl-tert-butyl ether, and pyridine. Examples of suitable tertiarybases include, e.g., methylmorpholine, pyridines, triethylamine,trimethylamine, ethylmethylpropylamine, DMAP, and disopropyl ethylamine.

In one embodiment, the invention further comprises the step ofprotecting the amino alcohol by silylation prior to reacting the aminoalcohol with the substituted aryl sulfonyl compound or substitutedheteroaryl sulfonyl compound. At the completion of the reaction, theproduct is deblocked to yield the desired substituted aryl orsubstituted heteroaryl sulfonamide.

The substituted aryl or substituted heteroaryl sulfonamide compoundsprepared using the 1S,2S-amino alcohols of the present invention haveutility for the prevention and treatment of disorders involving betaamyloid production including cerebrovascular diseases. The compounds ofthe present invention have utility for the prevention and treatment ofAD by virtue of their ability to reduce beta amyloid production.

The following examples are illustrative of the methods of synthesizing2S-amino alcohols according to the invention, and methods ofsynthesizing same. It will be readily understood by one of skill in theart that the specific conditions described herein for producing thesecompounds can be varied without departing from the scope of the presentinvention. It will be further understood that other compounds, as wellas other salts, hydrates, and/or prodrugs thereof, can be synthesizedusing the method of the invention.

EXAMPLES Example 1 Preparation of(2S,3S)-2-Amino-4,4,4-trifluoro-3-methyl-butan-1-ol HCl A. Preparationof(4S)-4-Benzyl-3-[(2E)-4,4,4-trifluoro-3-methyl-but-2-enoyl]-1,3-oxazolidin-2-one

(4S)-4-Benzyl-1,3-oxazolidin-2-one (828 g, 4.67 moles) was dissolved in6.8 L THF and cool to −40 to −50° C. To the solution of(4S)-4-benzyl-1,3-oxazolidin-2-one, 2.5 M BuLi in hexanes (1302 g, 1880mL, 4.70 mole, 1.01 equivalents) was added while keeping the temperatureat <−40° C. To the cold solution of the Li salt of(4S)-4-benzyl-1,3-oxazolidin-2-one, 4,4,4-trifluoro-3-methyl-2-butenoicacid chloride (887 g, 5.14 moles, 1.1 equivalents) was added over 10-30minutes, all-owing the temperature to rise and wash in with 0.4 L THF.The reaction was warmed to 20-25° C. and stirred for 2 h. 0.9 L waterwas added and stirred for 16 h. The THF was distilled off with a bathtemperature of 35° C. and vacuum<40 mm Hg. Toluene (5.8 L) was added andthe phases split. 4-L saturated NaHCO₃ was used to wash (2×), themixture was filtered through Celite and the phases split. 2.5-L water(2×) was used as a wash and the toluene layer was filtered throughCelite. The remaining water was removed. The toluene was distilled offwith a bath temperature of 40° C. and vacuum<40 mm Hg. At the end of thedistillation the product started to crystallize with a pot temperatureof 30° C. Distillation is continued to a pot temperature of 35° C.giving a solid mobile mass of 1456 g. The solid is dissolved in 2.9 L (2vol) EtOH (99.5% EtOH:0.5% toluene). While stirring at 20-25° C., water(1.09 L, 0.75 vol) was added over 1 h forming crystals. Stirring iscontinued for 16 h at 15-25° C., followed by cooling to 0-5° C. andholding for 1 h. The crystals are filtered, washed with filtrate anddried at 50° C. for 16 h giving 1229 g, 84% of(4S)-4-benzyl-3-[(2E)-4,4,4-trifluoro-3-methyl-but-2-enoyl]-1,3-oxazolidin-2-one.

B. Preparation of(4S)-4-Benzyl-3-[(3S)-4,4,4-trifluoro-3-methylbutanoyl]-1,3-oxazolidin-2-one

(4S)-4-Benzyl-3-[(2E)-4,4,4-trifluoro-3-methyl-but-2-enoyl]-1,3-oxazolidin-2-one(4) (1327 g, 4.24 mole) and 50.6 g of 5% Pd/C (50% wet) were added tothe hydrogenation vessel and purged with N₂ to remove air. 16.8 L ofEtOH (99.5% EtOH:0.5% toluene) was cooled to 0 to −5° C., added to thevessel and purged for hydrogenation while holding the temperature at 0to −5° C. The hydrogenation was started with 20 psig H₂ holding thetemperature at 0 to −5° C. for 17-34 h until the theoretical amount ofH₂ was consumed. The mixture was filtered through a 0.2μ filter and thefilter was washed with 24 L EtOAc. In order to remove Pd, it wasnecessary to remove the EtOH, replace it with toluene and filter thetoluene solution. The solvent was removed giving a solid that isdissolved in 6 L toluene, followed by stirring for 2 h at 0-5° C. andfiltering on a 1 kg Celite pad. Toluene (4 L) was used as a wash. Thetoluene was removed and 1 L EtOH added, followed by stirring at 10° C.for 2 h. Filtration and washing were with 0.2 L EtOH and 1 L heptane.Product was dried at 35° C. for 15 h giving 810 g 61% yield of 5 with SSto RS ratio of 96:4. The filtrate was concentrated to 412 g of a yellowsoft solid.

C. Preparation of di-tert-butyl1-((1S,2S)-1-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-carbonyl}-3,3,3-trifluoro-2-methylpropyl)hydrazine-1,2-dicarboxylate

(4S)-4-Benzyl-3-[(3S)-4,4,4-trifluoro-3-methylbutanoyl]-1,3-oxazolidin-2-one(5) (92% ee) (268.4 g, 0.851 mole) was dissolved in 1.8 L THF. Thesolution was stirred under N₂ and cooled to −75° C. At −70 to −76° C.add 2.0 M LDA in heptane/tetrahydrofuran/ethylbenzene (470 mL, 0.940mole, 1.1 equivalents) over 2 hours. The solution was stirred for 30minutes at <−70° C. Di-tert-butyl azodicarboxylate (240 g, 1.02 moles,1.2 equivalents) was dissolved in 900 mL THF and the solution cooled to0-5° C. A solution of 146 mL of glacial acetic acid was prepared in 200mL THF. The solution of di-tert-butyl azodicarboxylate was added rapidlyas possible maintaining the temperature at <−70° C. This usually takesabout 1 hour. After di-tert-butyl azodicarboxylate has been added, stirfor 3 minutes and the solution of acetic acid was added as rapidly aspossible letting the temperature rise as it is being added. The solutionis warmed to room temperature over a period of 2 hours. The flask wasprepared for distillation and the THF removed with a jacket temperatureof 35° C. at 60-70 mm Hg. 2 L toluene and 1.2 L water were added. Thelayers were separated and washed with 1 L water, 1 L 0.25 M HCl, twicewith 0.5 L saturated NaHCO₃ and twice with 0.5 L water. The toluenesolution was added to a flask prepared for vacuum distillation with ajacket temperature of 30° C. and 20-1 mm Hg. A quantitative yield of 7(464 g) as an oil is the usual result.

D. Preparation of di-tert-butyl1-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]hydrazine-1,2-dicarboxylate

The di-tert-butyl1-((1S,2S)-1-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-yl]-carbonyl}-3,3,3-trifluoro-2-methylpropyl)hydrazine-1,2-dicarboxylateoil (464 g, 0.851 mole) from step C was dissolved in 5.8 L of methylt-butyl ether (TBME) and 15.3 g water (0.851 mole, 1 equivalent) wasadded. The solution was cooled to 0-5° C. A solution of LiBH₄ (31.37 g,1.44 mole, 1.7 equivalents) in THF 690 mL was prepared by cooling theTHF to 0-10° C. and adding the LiBH₄ slowly under N₂. The LiBH₄ solutionwas added over 1 hour at 0-5° C. and washed in with 100 mL of TBME. Themixture is stirred for 16 hours warmed to room temperature. 2 L water isadded and stirred until gas evolution stops. A 1-L solution of 1 M HClwas prepared and added to the reaction mixture until it reached pH 1-2(about 850 mL was required). The aqueous phase were separated and theorganic phase washed twice with 1 L of water (pH 4 after the secondwash), 1 L of saturated NaHCO₃ diluted with water 9:1 (pH 9), twice with0.5 L brine and dried over 300 g MgSO₄. The solution was filtered. Thesolution was stripped until a solid was obtained under high vacuum (<10mm Hg) giving 420 g. 2.5 volumes (1050 mL) of CH₃CN was added andbrought to reflux to dissolve the solid. The solution was cooled to20-25° C. and stirred for 16 h. The solid was filtered and washed withCH₃CN giving 214.4 g, 68% yield. The m.p. must be >181° C. to assurechiral purity. HPLC was run to make sure no(4S)-4-Benzyl-1,3-oxazolidin-2-one was in the product.

E. Preparation of(2S,3S)-4,4,4-Trifluoro-2-hydrazino-3-methyl-butan-1-ol HCl

Di-tert-butyl1-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]hydrazine-1,2-dicarboxylate(214.4 g, 0.576 mole) was dissolved in 640 mL THF. The solution waswarmed to 30° C. and concentrated HCl (240 mL, 2.87 moles, 5equivalents) was added drop wise over 20 minutes at 30-50° C. Thesolution was maintained at 50° C. for 2 hours and the THF was removedwith aspirator vacuum at 30-60° C. The HCl solution was washed twicewith 300 mL TBME. The aqueous phase was then stripped to a white solidusing aspirator and vacuum pump at 50-60° C. The resulting solid wasdried at 50° C. under vacuum at <10 mm Hg giving 108.3 g, 90% yield of(2S,3S)-4,4,4-Trifluoro-2-hydrazino-3-methyl-butan-1-ol HCl.

F. Preparation of (2S,3S)-2-Amino-4,4,4-trifluoro-3-methyl-butan-1-olHCl

(2S,3S)-4,4,4-Trifluoro-2-hydrazino-3-methyl-butan-1-ol HCl (130 g,0.623 mole) was dissolved in 1.4 L MeOH with 60 mL concentrated HCl. Thesolution was hydrogenated with 10 g PtO₂ at 50 psig for 12 hours. Themixture was filtered and the filter washed with 1 L MeOH. The MeOH wasremoved to dryness under vacuum at 30-40° C. The solid was chased withtwo portions of 1 L MeOH. The solid was stirred with 0.5 L MeOH for 1hour and the NH₄Cl was removed by filtration. To remove more NH₄Cl, thefiltrate can be concentrated to ⅔ volume and crystallized NH₄Cl removedby filtration. The filtrate was concentrated to dryness and dried at 35°C. at <10 mm Hg. The hydrochloride can be purified by stirring with 20%v/v CH₃CN: EtOAc removing a green coloring and removing essentially allthe Pt to the 10 ppm level.

Example 2 Preparation of5-Chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide

(2S,3S)-2-Amino-4,4,4-trifluoro-3-methyl-butan-1-ol HCl (10) (385.5 g,1.99 moles) was stirred with 3.8 L CH₂Cl₂ and 1007 g (9.96 mole,equivalents) 1-methylmorpholine was added with a wash of 200 mL CH₂Cl₂.At 20-30° C., Me₃SiCl (443 g, 4.08 mole, 2.05 equivalents) was over15-30 minutes. The solution was stirred for 1 h at 20-30° C., thencooled to 15-20° C. 454 g (2.09 moles, 1.05 equivalents) of5-chloro-thiophene-2-sulfonyl chloride was added over 10-15 minutes at18 to 24° C. and washed with 190 mL CH₂Cl₂. The temperature rose to31.5° C. over 30 minutes with the reactor in a bath at 30° C. Themixture was stirred for 16 hours and tested by HPLC to assure thatexcess (1-10%) 5-chloro-thiophene-2-sulfonyl chloride remains. 22 mL1-methylpiperazine (0.199 mole, 0.1 equivalents) was added. The solventwas removed by distillation under vacuum at 90 mm Hg in a bath at 20-30°C. 3.65 L isopropyl acetate and 2 N H₂SO₄ (2 L) were added, the mixturewas stirred for 20 minutes and the layers separated. The aqueous layerwas back extracted with 0.5 L isopropyl acetate. 2 L 2 N H₂SO₄, 2 L ½saturated NaHCO₃ and 2 L water were used as a wash. The layers wereclarified by filtration through 0.2 μM filter. The isopropyl acetate wasremoved under vacuum (40 to <10 mm Hg) to dryness giving 675 g of crude5-Chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide.The product was recrystallized from 10 volumes of 1:4 EtOAc/Heptanesgiving 499 g after drying at 55° C. for 16 hours. A second crop of 49 gmay be obtained from the mother liquors for a total yield of 548 g, 81%.

All publications cited in this specification are incorporated herein byreference. While the invention has been described with reference to aparticularly preferred embodiment, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

1. A method of preparing a compound of the formula:

wherein R₁ and R₂ are CF₃; said method comprising: (a) reacting acompound of the following structure:

wherein R″ is benzyl, phenyl, or isopropyl; with an azo dicarboxylatecompound of the structure:

wherein R′″ is alkyl or benzyl; to afford a compound of the structure:

(b) reducing the product of step (a) to a compound of the structure:

(c) deblocking the product of step (b) with an acid to yield a compoundof the following structure:

(d) hydrogenating the product of step (c) in the presence of a metalcatalyst.
 2. The method according to claim 1, further comprisingtriturating the product of step (d) in a solvent to remove trapped metalcontaminants from the catalyst.
 3. The method according to claim 1,wherein step (a) is performed under cold conditions.
 4. The methodaccording to claim 1, wherein step (a) is performed using lithiumdiisopropyl amide or potassium bis(trimethyl)silylamide in a solvent. 5.The method according to claim 4, wherein the solvent comprisestetrahydrofuran.
 6. The method according to claim 4, wherein step (a)further comprises quenching the reaction with glacial acetic acid. 7.The method according to claim 1, wherein step (b) is performed usingLiBH₄ in tetrahydrofuran and water or t-butyl methyl ether and water. 8.The method according to claim 1, wherein said acid in step (c) is HCl.9. The method according to claim 8, wherein concentrated HCl is added tothe dicarboxylate at 30° C. to 50° C.
 10. The method according to claim1, wherein said catalyst in step (d) is selected from the groupconsisting of PtO₂, PdO₂, and RaNi.
 11. A method of preparing a compoundof the structure:

wherein R₁ and R₂ are CF₃; said method comprising: (a) reacting acompound of the following structure:

wherein R″ is benzyl, phenyl, or isopropyl; with an azo dicarboxylatecompound of the structure:

wherein R′″ is alkyl or benzyl; to afford a compound of the structure:

(b) reducing the product of step (a) to a compound of the structure:

(c) deblocking the product of step (b) with an acid to yield a compoundof the following structure:

(d) hydrogenating the product of step (c) in the presence of a metalcatalyst to form a compound of the following structure:

and (e) reacting the product of step (d) with5-chlorothiophene-2-sulfonylchloride.
 12. The method according to claim11, further comprising: (i) protecting the product of step (d) bysilylation prior to step (e); and (ii) deblocking the product of step(i).
 13. The method according to claim 11, further comprisingtriturating the product of step (d) in a solvent to remove trapped metalcontaminants from the catalyst.
 14. The method according to claim 11,wherein step (a) is performed under cold conditions.
 15. The methodaccording to claim 11, wherein step (a) is performed using lithiumdiisopropyl amide or potassium bis(trimethyl)silylamide in a solvent.16. The method according to claim 15, wherein the solvent comprisestetrahydrofuran.
 17. The method according to claim 15, wherein step (a)further comprises quenching the reaction with glacial acetic acid. 18.The method according to claim 11, wherein step (b) is performed usingLiBH₄ in tetrahydrofuran and water or t-butyl methyl ether and water.19. The method according to claim 11, wherein said acid in step (c) isHCl.
 20. The method according to claim 19, wherein concentrated HCl isadded to the dicarboxylate at 30° C. to 50° C.
 21. The method accordingto claim 11, wherein said catalyst in step (d) is selected from thegroup consisting of PtO₂, PdO₂, and RaNi.
 22. The method according toclaim 11, wherein step (e) is performed in dichioromethane.